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A Critical Role for Dorsal Progenitors in Cortical Myelination

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A Critical Role for Dorsal Progenitors in Cortical Myelination The Journal of Neuroscience, January 25, 2006 • 26(4):1275–1280 • 1275 Brief Communication A Critical Role for Dorsal Progenitors in Cortical Myelination Tao Yue,1 Kendy Xian,1 Edward Hurlock,1 Mei Xin,1,3 Steven G. Kernie,1,2 Luis F. Parada,1 and Q. Richard Lu1,3 1Center for Developmental Biology and Kent Waldrep Foundation Center for Basic Neuroscience Research on Nerve Growth and Regeneration, 2Department of Pediatrics, and 3Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 Much controversy regarding the anatomical sources of oligodendrocytes in the spinal cord and hindbrain has been resolved. However, the relative contribution of dorsal and ventral progenitors to myelination of the cortex is still a subject of debate. To assess the contribu- tion of dorsal progenitors to cortical myelination, we ablated the basic helix-loop-helix transcription factor Olig2 in the developing dorsal telencephalon. In Olig2-ablated cortices, myelination is arrested at the progenitor stage. Under these conditions, ventrally derived oligodendrocytes migrate dorsally into the Olig2-ablated territory but cannot fully compensate for myelination deficits observed at postnatalstages.Thus,spatiallyrestrictedablationofOlig2functionunmasksacontributionofdorsalprogenitorstocorticalmyelination that is much greater than hitherto appreciated. Key words: cortex; knock-out mice; oligodendrocyte; bHLH transcription factor; Olig2; myelination Introduction cells in the forebrain of rodent neonates and in vitro cortical Cortical myelination by oligodendrocytes facilitates the forma- progenitor culture data suggest that oligodendrocytes can be de- tion of a highly complex but organized brain structure in verte- rived from the dorsal telencephalon (Levison and Goldman, brates (Zalc and Colman, 2000). Failure of oligodendrocyte dif- 1993; Gorski et al., 2002; Ivanova et al., 2003). Nonetheless, the ferentiation may contribute to many neurological diseases such extent and timing that dorsal progenitor cells contribute to cor- as the demyelinating disease multiple sclerosis (Noseworthy et tical oligodendrogenesis during brain development remain al., 2000; Franklin, 2002). In the developing brain, oligodendro- unknown. cyte precursor cells (OPCs) are derived from neural progenitors Olig2, a member of the basic helix-loop-helix Olig transcrip- present in the ventricular and subventricular zones at early devel- tion factor family, plays a critical regulatory role in oligodendro- opmental stages with their maturation and myelination following glial cell fate specification in the developing spinal cord (Rowitch, at postnatal stages (Sauvageot and Stiles, 2002; Miller and Reyn- 2004). Olig gene expression in the CNS persists through adult- olds, 2004; Goldman, 2005). hood (Lu et al., 2000; Zhou et al., 2000), wherein it may partici- Much of the controversy regarding the origins of oligoden- pate in the glial response to injury and in brain repair (Arnett et drocytes in the spinal cord and hindbrain has been recently re- al., 2004; Fancy et al., 2004; Balabanov and Popko, 2005). Gene- solved with the discovery of a late-arising pool of dorsal progen- targeting studies show that Olig2 is essential for the formation of itors that contribute to a larger population of oligodendrocytes oligodendrocytes and motor neurons in the spinal cord (Lu et al., derived from progenitors in the ventral neural tube (Cai et al., 2002; Takebayashi et al., 2002; Zhou and Anderson, 2002). How- 2005; Fogarty et al., 2005; Miller, 2005; Vallstedt et al., 2005). ever, neonatal lethality of Olig2 knock-out mice impedes the However, the relative contribution of dorsal and ventral progen- study of Olig2 function in oligodendrocyte myelination during itor cells to oligodendrocyte myelination in the cortex is highly postnatal brain development. In this study, we generated a con- contended in the brain development field (Spassky et al., 2000; ditional Olig2 allele using the Cre/lox system by flanking the Olig2 Woodruff et al., 2001; Marshall et al., 2003; Miller, 2005). A cur- coding region on mouse chromosome 16 with loxP sites (see Fig. rent view suggests that the majority of cortical oligodendrocytes 1A–D). Utilizing the critical requirement of Olig2 in oligoden- are initially derived from the ventral telencephalon, populating drocyte specification, we examined the role of dorsal progenitors the dorsal regions by migration and proliferation (Woodruff et in cortical myelination by deleting Olig2 in these progenitors. al., 2001). Intriguingly, the fate-mapping analysis of progenitor Olig2 ablation mediated by cortical progenitor-restricted Cre re- combinases results in severe myelination defects in the cortex, and the myelination deficit cannot be fully compensated for by Received Nov. 3, 2005; revised Dec. 11, 2005; accepted Dec. 18, 2005. This work was supported by grants from the Wadsworth Foundation, National Multiple Sclerosis Society and ventrally derived oligodendrocytes. Thus, spatially restricted ab- March of Dimes Birth Defect Foundation and by National Institutes of Health Grant R01 NS050389 (Q.R.L.). Q.R.L. is lation of Olig2 function unmasks an important contribution of a Harry Weaver Neuroscience Scholar and a Basil O’Conner Scholar. We thank Drs. Albee Messing, Susan McConnell, dorsal progenitors to cortical myelination. Takuji Iwasato, and Philip Soriano for hGFAP-Cre, Foxg1-Cre, Emx1-Cre, and Rosa26 reporter mice, respectively. We appreciate Drs. Ben Barres and James Goldman for discussion. We are grateful to Dr. Chuck Stiles for support and Materials and Methods reagents. Correspondence should be addressed to Dr. Q. Richard Lu, Center for Developmental Biology, University of Texas Generation of Olig2 conditional mutant mice. To construct the floxed Southwestern Medical Center, Dallas, TX 75390. Email: [email protected]. Olig2 targeting vector, we inserted two loxP sites to flank the Olig2 coding DOI:10.1523/JNEUROSCI.4717-05.2006 region, followed by a neomycin selection cassette, into a 10 kb SacI–SacII Copyright © 2006 Society for Neuroscience 0270-6474/06/261275-06$15.00/0 genomic fragment in the pKO-915 vector (Stratagene, La Jolla, CA). The 1276 • J. Neurosci., January 25, 2006 • 26(4):1275–1280 Yue et al. • Dorsal Progenitors for Cortical Myelination Figure 1. Conditional ablation of Olig2 in cortical progenitors. A, Olig2 conditional knock-out mice are generated through homologous recombination in embryonic stem cells with the Olig2-coding region flanked by two loxP sites. B, Generation of Olig2-ablated alleles by Cre-mediated loxP site recombination preceded by Flpase-mediated FRT site recombination of the neomycin selectioncassetteinthetargetedgenome.C,Olig2mutantalleleswereconfirmedbySouthernblotwitha5Јexternalprobe(wild-typeandmutantfragmentsizes;5and7kb,respectively).D,Olig2 mutant alleles are confirmed by PCR analysis [wt ϩ/ϩ, 100 bp; Olig2 mutant (c/ϩ and c/c), 150 bp]. E, Coronal sections of hGFAPCre forebrain at E14.5 were immunostained with a Cre antibody. Red and white arrows indicate the subventricular zone of the dorsal telencephalon and the ganglionic eminence, respectively. F, ␤-Galactosidase activity in the forebrain of hGFAPCre;Rosa26 mice atE14.5.Redandgreenarrowsindicatethedorsalandventralofforebrain,respectively.G–N,ExpressionofOlig2andPdgf␣RmRNAs(arrows)intheforebrainofOlig2c/-;hGFAPCre (CkoG)andcontrol mice (ctrl, Olig2c/ϩ;hGFAPCre) was analyzed by in situ hybridization at E14.5 and E16.5 as indicated. targeting vector was linearized with NotI and electroporated into mouse ondary antibodies conjugated to Cy2 or Cy3 (Jackson ImmunoResearch, J1 embryonic stem cells and G418-resistant cells were selected. Genomic West Grove, PA) were used for double-labeling experiments. Microscopy DNA from drug-resistant cells was digested with HindIII and analyzed by was performed on a Zeiss (Oberkochen, Germany) LSM 510 confocal Southern blot using a 0.5 kb or HindIII–SacI fragment as a 5Ј probe for microscope. Olig2. Transmission of the target allele through the germline was con- Electron microscopy. Electron microscopy was performed as described firmed by Southern blot. Subsequently a PCR strategy was used to iden- previously. Briefly, the corpus callosum of forebrains from control and tify the mutants. PCR primers 5Ј and 3Ј are agc cag ccc tca ctt gga gaa ctg Olig2-ablated mice were dissected and fixed overnight by a fixative con- ggc ctg and cgc tag agc ctg ttt tgc acg ttc acc, respectively. The sizes of PCR taining 2% glutaraldehyde in 0.1 M cacodylate, pH 7.2. Cross sections of products for conditional mutants (cko) and wild-types are 350 and 150 these tissues were processed and thin sections were cut for electron bp respectively. Olig2 mutant mice, Cre activator lines, and Rosa26 re- microscopy. porter lines were maintained on a C57BL6/J and 129 SVJ hybrid back- ground. All protocols involving the use of animals were approved by the Results Institutional Animal Care and Research Advisory Committee at Univer- Olig2 ablation in cortical progenitor cells does not prevent sity of Texas Southwestern Medical Center at Dallas. OPC formation RNA in situ hybridization. Olig2 control and mutant brains from em- Olig2 ablation in the dorsal telencephalon is initiated by an bryonic and postnatal stages were harvested from anesthetized mice. hGFAPCre deleter line (Zhuo et al., 2001) (Fig. 1B). At embryonic They were fixed in 4% paraformaldehyde at 4°C overnight, cryopro- stages, the Cre recombinase is predominantly
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